PROJECT SUMMARY People with schizophrenia have a broad range of cognitive impairments, which are major determinants of the poor functional outcome observed in people with this disorder. Unfortunately, pharmacological and non- pharmacological interventions have limited benefits for these impairments. In the absence of effective treatments, cognitive impairments remain a critical unmet therapeutic need, and the development of novel approaches for their treatment remains a central therapeutic challenge. Over the past 10 years, considerable evidence has emerged to suggest that the gut microbiota has significant effects on brain development and behavior, in part, through the regulation of immune system function. The gut microbiota affects immune system function through the production of short chain fatty acids (SCFAs) and other mechanisms. There are three major SCFAs: butyrate, propionate, and acetate, of which, butyrate appears to have the most pronounced effects on the immune system. Prebiotics are dietary fibers that promote the growth or activity of gut microorganisms, which leads to enhanced well-being of the host; they have been shown to increase the activity of multiple different bacteria species, including butyrate-producing bacteria. In light of the emerging evidence that suggests schizophrenia is characterized by multiple abnormalities of the immune system, which lead to a pro-inflammatory state, the proposed R61 and R33 projects are designed to evaluate the hypothesis that prebiotic administration will lead to increased production of butyrate, through increased activity of butyrate- producing bacteria in the gut microbiota; the increase in serum butyrate levels will be associated with changes in cognitive function, symptoms, and metabolic measures. In the R61 project, we will conduct a 10-day, double-blind, placebo-controlled, randomized clinical trial (RCT) to determine if the prebiotic: Prebiotin (12g/day), an oligofructose-enriched inulin (FOS), alters the hypothesized biological signature, i.e., increases serum butyrate levels. We will use an inulin-challenge paradigm to asses the effect of FOS on serum butyrate levels. In the R33 project, we will conduct a 12-week, double-blind, placebo-controlled, RCT, to confirm the ability of the prebiotic: FOS (12g/day), to alter the hypothesized biological signature: serum butyrate levels. We will also examine the extent to which changes in serum butyrate levels are associated with changes in cognitive function, symptoms, and metabolic measures. We will use the MATRICS Consensus Cognitive Battery to assess change in cognitive function. The study will provide critical preliminary data on the clinical utility of prebiotic treatment for the improvement of cognitive function in people with schizophrenia.